Doxorubicin and taxane combination regimens for metastatic breast cancer: Focus on cardiac effects

Investigation of the combination of the taxanes with doxorubicin in the treatment of breast cancer has logically progressed, with the ultimate goal of identifying a safe and effective regimen for use in the adjuvant setting. Initial phase II findings of the concurrent doxorubicin/paclitaxel combination resulted in substantial response rates, but at a high cost. A much higher percentage of patients than expected developed anthracycline-induced cardiomyopathy. Subsequent phase II and phase III trials have determined administration schedules of doxorubicin/paclitaxel that reduce the risk for cardiotoxicity. However, the overall response rate is only modestly improved over sequential single-agent therapy or standard doxorubicin-containing combination therapy. The lack of cardiotoxicity with docetaxel, its high antitumor activity, and its linear pharmacokinetics have made it an attractive taxane for combination with doxorubicin. In addition, it is easily administered in the outpatient setting. Phase I/II trials of the combination of doxorubicin/docetaxel resulted in high response rates with a lack of adverse modification of anthracycline-induced cardiomyopathy. These findings have been confirmed in a large phase III randomized trial where overall response rates and time to disease progression were significantly improved, but the incidence of cardiomyopathy was not different for the doxorubicin/docetaxel versus doxorubicin/cyclophosphamide (AC) regimen. Ongoing studies are underway to assess the role of the doxorubicin/docetaxel combination in the adjuvant setting as primary chemotherapy in the neoadjuvant setting. It is here that the most benefit on survival of breast cancer patients is likely to be shown. At the same time, it is in the adjuvant setting where the absence of potentially late cardiac and other toxicities must be assured.